Drug Incorporation Models and Release

Three different models of how drugs can be incorporated into SLNs have been developed. The first particles produced were characterized by a burst release; a first in vitro prolonged release was reported for particles loaded with prednisolone [5]. Basically, three incorporation models are proposed [30]:

1. drug-enriched shell type

2. drug-enriched core type

3. homogeneous matrix of solid solution.

These incorporation models are shown in Figure 1. The type of SLN depends on the chemical nature of the drug and lipid, the solubility of drug in the melted lipid, the nature and concentration of surfactants, the type of production (hot versus cold homogenization), in general from the production temperature.

A drug enrichment in the shell is achieved when SLNs are produced via the hot homogenization technique and the drug concentration in the melted lipid is low. During the cooling process of the hot o/w nanoemulsion, the lipid will precipitate first, leading to a steadily increasing concentration of drug in the remaining lipid melt with an increasing fraction of lipid solidified. A drug-free lipid core is formed when the drug reaches its saturation solubility in the remaining melt; an outer shell will solidify, containing both drug and lipid. The enrichment in the outer area of the particles causes a burst release.

Drug enrichment in the core can take place when the drug concentration in the lipid melt is high and at the (or relatively close to) saturation solubility. Cooling down of the hot oil droplets will, in most cases, reduce the solubility of the drug in the melt; when the saturation solubility is exceeded, the drug precipitates, and leads to the formation of a drug-enriched core.

A solid solution can be obtained when SLNs are produced by the cold homogenization method. A lipid blend can be produced, containing the drug in a molecular disperse form. After solidification of this blend, it is ground in its solid

drug-enriched drug-enriched matrix shell core

Figure 1. Incorporation models for SLNs. Drug-enriched shell (left), drug-enriched core (middle), and homogeneous matrix (right).

drug-enriched drug-enriched matrix shell core

Figure 1. Incorporation models for SLNs. Drug-enriched shell (left), drug-enriched core (middle), and homogeneous matrix (right).

state, thus avoiding or minimizing the enrichment of drugs in different parts of the lipid particle. The percentage of drug localized in the outer shell can be adjusted in a controlled way by altering the production parameters.

Figure 2 shows the redistribution effect occurring during the SLN production by the hot homogenization technique [31]. Dispersing the drug-containing lipid melt in a hot aqueous surfactant solution will lead to a distribution of the drug into the aqueous phase (according to the solubility and partitioning coefficient). If the aqueous phase contains a higher surfactant concentration, in most cases, this leads to a better solubility of the lipophilic drug in the water phase (e.g., by solubilization), and thus, a more pronounced distribution of drug to the water phase. Furthermore, the solubility in the water phase can be further increased by choosing higher production temperatures; thus, even more of the drug will go to the water phase. An opposite effect occurs when the produced hot nanoemulsion is in the cooling process. The solubility in the aqueous phase decreases. Lipids starts to precipitate, forming a lipid core with a lower drug concentration than in the original drug-containing lipid melt. Further cooling leads to a further reduction of the drug solubility in the water phase, and redistribution back to the lipid phase; however, due to the formation of the solid lipid core, only the outer shell is accessible for the drug to localize. In general, most of this drug is considered to be released in the form of a burst. This means that the extent of burst can be controlled by controlling the amount of drug in the shell. zur Mühlen and Mehnert [30] could show nicely the dependence of the extent of burst release as a function of production temperature and surfactant concentration. Burst release can be avoided by the cold homogenization technique.

To summarize, the drug-release profile depends on the type/structure of the SLN nanoparticle created. This allows adjustment of the drug-release profile by controlled production of a certain SLN type. Especially for active compounds which should exhibit a prolonged/very little release, the drug-enriched core type is most suitable, for example, molecular sunscreens [32].

hot cold diffusion of drug into repartitioning of drug aqueous emulsifier solution into particle hot cold diffusion of drug into repartitioning of drug aqueous emulsifier solution into particle

liquid state of lipid recrystallisation of lipid

Figure 2. Redistribution effects during the production process of SLNs using the hot homogenization technique. For explanations, see text. Adapted with permission from [31], R. H. Müller et al., Adv. Drug Del. Rev. 54, S131 (2002). © 2002, Elsevier.

liquid state of lipid recrystallisation of lipid

Figure 2. Redistribution effects during the production process of SLNs using the hot homogenization technique. For explanations, see text. Adapted with permission from [31], R. H. Müller et al., Adv. Drug Del. Rev. 54, S131 (2002). © 2002, Elsevier.

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